Cardiac Arrest, or Sudden Death, is a descriptor for a diverse collection of physiological abnormalities with a common cardiac aetiology, wherein the patient typically presents with the symptoms of pulselessness, apnoea, and unconsciousness. Cardiac arrest is widespread, with an estimated 300,000 victims annually in the U.S. alone and a similar estimate of additional victims worldwide. Early defibrillation is the major factor in sudden cardiac arrest survival. There are, in fact, very few cases of cardiac arrest victims saved which were not treated with defibrillation. There are many different classes of abnormal electrocardiographic (ECG) rhythms, some of which are treatable with defibrillation and some of which are not. The standard terminology for this is “shockable” and “non-shockable” ECG rhythms, respectively. Non-shockable ECG rhythms are further classified into hemodynamically stable and hemodynamically unstable rhythms. Hemodynamically unstable rhythms are those which are incapable of supporting a patient's survival with adequate blood flow (non-viable). For example, a normal sinus rhythm is considered non-shockable and is hemodynamically stable (viable). Some common ECG rhythms encountered during cardiac arrest that are both non-shockable and hemodynamically unstable are: bradycardia, idioventricular rhythms, pulseless electrical activity (PEA) and asystole. Bradycardias, during which the heart beats too slowly, are non-shockable and also possibly non-viable. If the patient is unconscious during bradycardia, it can be helpful to perform chest compressions until pacing becomes available. Idioventricular rhythms, in which the electrical activity that initiates myocardial contraction occurs in the ventricles but not the atria, can also be non-shockable and non-viable (usually, electrical patterns begin in the atria). Idioventricular rhythms typically result in slow heart rhythms of 30 or 40 beats per minute, often causing the patient to lose consciousness. The slow heart rhythm occurs because the ventricles ordinarily respond to the activity of the atria, but when the atria stop their electrical activity, a slower, backup rhythm occurs in the ventricles. Pulseless Electrical Activity (PEA), the result of electro-mechanical dissociation (EMD), in which there is the presence of rhythmic electrical activity in the heart but the absence of myocardial contractility, is non-shockable and non-viable and would require chest compressions as a first response. Asystole, in which there is neither electrical nor mechanical activity in the heart, cannot be successfully treated with defibrillation, as is also the case for the other non-shockable, non-viable rhythms. Pacing is recommended for asystole, and there are other treatment modalities that an advanced life support team can perform to assist such patients, e.g. intubation and drugs. The primary examples of shockable rhythms that can be successfully treated with defibrillation are ventricular fibrillation, ventricular tachycardia, and ventricular flutter.
Normally, electrochemical activity within a human heart causes the organ's muscle fibers to contract and relax in a synchronized manner. This synchronized action of the heart's musculature results in the effective pumping of blood from the ventricles to the body's vital organs. In the case of ventricular fibrillation (VF), however, abnormal electrical activity within the heart causes the individual muscle fibers to contract in an unsynchronized and chaotic way. As a result of this loss of synchronization, the heart loses its ability to effectively pump blood. Defibrillators produce a large current pulse that disrupts the chaotic electrical activity of the heart associated with ventricular fibrillation and provides the heart's electrochemical system with the opportunity to re-synchronize itself. Once organized electrical activity is restored, synchronized muscle contractions usually follow, leading to the restoration of effective cardiac pumping.
First described in humans in 1956 by Dr. Paul Zoll, transthoracic defibrillation has become the primary therapy for cardiac arrest, ventricular tachycardia (VT), and atrial fibrillation (AF). Monophasic waveforms dominated until 1996, when the first biphasic waveform became available for clinical use. Attempts have also been made to use multiple electrode systems to improve defibrillation efficacy. While biphasic waveforms and multiple-electrode systems have shown improved efficacy relative to monophasic defibrillation, there is still significant room for improvement: shock success rate for ventricular fibrillation (VF) remains less than 70% even with the most recent biphasic technology. In these cases, shock success was defined to be conversion of a shockable rhythm into a non-shockable rhythm, including those non-shockable rhythms which are also non-viable. Actual survival-to-hospital-discharge rates remain an abysmal ten percent or less. Survival rates from cardiac arrest remain as low as 1-3% in major U.S. cities, including those with extensive, advanced prehospital medical care infrastructures.
Approximately 40-50% of cardiac arrest victims are resuscitated by paramedics and emergency medical technicians (EMTs) in the field and brought to the hospital for further treatment; however, due to the insult on the victim's vital organs from the cardiac arrest, typically only about 25% (or approximately 40,000 out of 600,000 cardiac arrest victims, worldwide) of those victims who survive to the hospital will survive to being discharged from the hospital.
The treatment window for cardiac arrest with current treatments of defibrillation, cardiopulmonary resuscitation, and inotropic (e.g. epinephrine) drug treatment is very narrow. Long term survival rates from the time of victim collapse decrease at a roughly exponential rate with a time constant of roughly 2 minutes. Thus, just two minutes of delay in treatment using the currently recommended treatment protocols result in a long term survival rate of 30-35%. After 15 minutes, the long term survival rates are below 5%. While the response times of emergency medical systems have improved significantly over the last quarter century to the point that average times from emergency call to arrival at the victim is typically 9 minutes or less, bystander delays in making the emergency call typically add 2-3 minutes to the total arrest time, for a total of 11-12 minutes. In addition, the bystander making the emergency call may not even have witnessed the cardiac arrest, which may have occurred at some point in the past. Unwitnessed arrest accounts for at least half of all cardiac arrests. Cardiac arrest downtimes are only reported for witnessed arrests; it has been estimated, however, that if unwitnessed arrests were to be included, the average downtime for all victims would exceed 15 minutes. At the time of initial collapse, the ECGs of nearly all cardiac arrest victims are shockable rhythms such as VF or VT; after 15 minutes, however, the ECG rhythms of most cardiac arrest victims have degenerated into the non-shockable rhythms of PEA or asystole. Attempts to reduce this response time through the widespread adoption of AEDs has been minimally successful, at best, for a variety of economic and social factors. It would be thus advantageous to have treatment methods available to deal with cardiac arrest victims with profound ischemia due to long downtimes.
During cardiac arrest, cerebral blood flow ceases and global cerebral hypoxic-ischemic injury begins within minutes. Myocardial and neuronal tissue is able to remain viable during prolonged periods of ischemia—as long as twenty minutes, but paradoxically will sustain immediate damage during the return of circulation and oxygenation. It has been shown in a variety of studies at the tissue-level and animal model that successful resuscitation with return of spontaneous circulation (ROSC) leads to a secondary cascade of injury related to reperfusion injury. This reperfusion injury is particularly acute in neuronal tissue. When neurons and myocytes shift to anaerobic metabolism as a result of oxygen depletion, during the course of ATP hydrolysis lactate is converted to lactic acid, H+ is generated, and intracellular pH drops. This activates the sodium/hydrogen (NaH) exchange ion channels, which, however, require ATP and thus become depressed during ischemia. There is thus a build-up of intracellular H+ during ischemia. During reperfusion, the NaH exchange channel is reactivated causing a net influx of sodium which then causes a net influx of calcium via the sodium/calcium (NCX) exchange channel in order to exteriorize the elevated sodium ions. Elevation of intracellular calcium can lead to an accumulation of this ion by mitochondria, with activation of mitochondrial permeability transition (MPT).
During reperfusion, intracellular levels of glutamate, an excitatory neurotransmitter released from presynaptic terminals, increases markedly. Glutamate activates ion channel complexes, particularly the N-methyl-D-aspartate (NMDA) receptors, which when activated increase calcium conductance from the extracellular to intracellular fluid. Mitochondrial calcium increases, resulting in the formation of reactive oxygen species. Both mitochondrial calcium overload and ROS production initiate the formation of large pores in the mitochondrial membrane. Opening of high-conductance mitochondrial transition pores (MTP) in the mitochondrial inner membrane initiates onset of the mitochondrial permeability transition (MPT). The MTP pores conduct both positively and negatively charged solutes of up to 1,500 Da. Pore opening causes the collapse of mitochondrial membrane potential and cessation of mitochondrial ATP production. In addition, multiple biochemical cascades lead to the production of oxygen free-radicals and the activation of proteases, endonucleases, phospholipases and xanthine oxidase which cause destruction of cell membranes and other essential cytoskeletal structures such as microtubules. Even if these events are not immediately fatal to the cell, some neurons later undergo programmed cell death (apoptosis).
After successful cardiac resuscitation and ROSC, cerebral blood flow may remain abnormally low for several hours. After an initial hyperemia resulting from high circulating levels of catecholamines, cerebral blood flow decreases just as the cerebral metabolic rate for oxygen increases. This can lead to a prolonged state of relative cerebral ischemia. This prolonged mismatch between cerebral metabolic rate and blood flow, and ongoing biochemical and molecular processes related to delayed neuronal apoptotic and necrotic cell death, provide the scientific rationale for induced hypothermia as a form of neuroprotection after cardiac arrest. One method developed is the cooling of comatose cardiac arrest survivors to approximately 34 degrees Celsius within 4 hours of arrest onset. The exact mechanism for the therapeutic effects of hypothermia is not fully understood, but has been shown in several studies to enhance the survival rates of patients who are initially resuscitated (the approximately 40-50% of victims making it to the hospital). Hypothermia is common in the cardiac intensive care, hospital environment such as in bypass operations, etc, but there are two related drawbacks of hypothermia which have prevented its widespread use in the pre-hospital environment.
The first of these drawbacks is the primary biomedical engineering challenge of hypothermia: the large thermal mass of the victim and the difficulty of cooling the victim quickly and safely. While it has been shown that hypothermia is beneficial as long as it is applied within 4 hours of cardiac arrest, studies have also shown that cooling prior to resuscitation provides additive therapeutic benefits. While the causes for this are only speculative, one of the factors is likely the positive effects of hypothermia during the reperfusion phase of resuscitation. Practically speaking, it is highly undesirable to delay defibrillation and resuscitation to cool a patient to the proper temperature. Non-invasive methods of cooling take at minimum 10 minutes to 1 hour, while invasive methods such as extraction and cooling of the blood may take only 3-5 minutes, but are hazardous to the patient, particularly in the pre-hospital environment. In the case of defibrillation, even a delay of 3 minutes can result in a decrease in survival of 30%. While hypothermia may be effective at counteracting longer-term deleterious effects of ischemia and reperfusion, it would be desirable to have a treatment that can provide immediate protective effects against reperfusion injury while, at the same time, not delaying any current resuscitation interventions.
The mechanisms allowing prolonged cell survival during ischemia and minimizing lethal cell injury after reperfusion remain incompletely understood. It has been shown in studies that the naturally occurring acidosis of ischemia, like hypothermia, strongly protects renal cells, myocytes, and hepatocytes against ischemia-induced cell death. In contrast, the return of extracellular pH to physiological levels is an event that actually precipitates lethal cell injury, termed the “pH paradox”. It has been hypothesized by researchers that the pH dependency of reperfusion injury may be the consequence of the pH dependency of the MTP opening. Conductance of the NMDA channel is also known to decrease steeply when extracellular pH is reduced below 7.0. Intracellular pH may also be important; intracellular acidosis during and after simulated ischemia and reperfusion has been shown to protect cultured cardiac myocytes against injury. Increased extracellular proton concentration will also minimize the inward sodium influx via the Na—H exchange ion channels, thereby reducing the intracellular sodium concentrations and the net influx of calcium via the sodium-calcium exchanger channels, and thus minimizing calcium overload.
Ventilation is a key component of cardiopulmonary resuscitation during treatment of cardiac arrest. Venous blood returns to the heart from the muscles and organs depleted of oxygen (O2) and full of carbon dioxide (CO2). Blood from various parts of the body is mixed in the heart (mixed venous blood) and pumped to the lungs. In the lungs the blood vessels break up into a net of small vessels surrounding tiny lung sacs (alveoli). The net sum of vessels surrounding the alveoli provides a large surface area for the exchange of gases by diffusion along their concentration gradients. A concentration gradient exists between the partial pressure of CO2 (PCO2) in the mixed venous blood (PvCO2) and the alveolar PCO2. The CO2 diffuses into the alveoli from the mixed venous blood from the beginning of inspiration until an equilibrium is reached between the PvCO2 and the alveolar PCO2 at some time during the breath. When the subject exhales, the first gas that is exhaled comes from the trachea and major bronchi which do not allow gas exchange and therefore will have a gas composition similar to the inhaled gas. The gas at the end of this exhalation is considered to have come from the alveoli and reflects the equilibrium CO2 concentration between the capillaries and the alveoli; the PCO2 in this gas is called end-tidal PCO2 (PEtCO2).
When the blood passes the alveoli and is pumped by the heart to the arteries it is known as the arterial PCO2 (PaCO2). The arterial blood has a PCO2 equal to the PCO2 at equilibrium between the capillaries and the alveoli. With each breath some CO2 is eliminated from the lung and fresh air containing little or no CO2 (CO2 concentration is assumed to be 0) is inhaled and dilutes the residual alveolar PCO2, establishing a new gradient for CO2 to diffuse out of the mixed venous blood into the alveoli. The rate of breathing, or minute ventilation (V), usually expressed in L/min, is exactly that required to eliminate the CO2 brought to the lungs and maintain an equilibrium PCO2 (and PaCO2) of approximately 40 mmHg (in normal humans). When one produces more CO2 (e.g., as a result of fever or exercise), more CO2 is produced and carried to the lungs. One then has to breathe harder (hyperventilate) to wash out the extra CO2 from the alveoli, and thus maintain the same equilibrium PaCO2. But if the CO2 production stays normal, and one hyperventilates, then the PaCO2 falls. Conversely, if CO2 production stays constant and ventilation falls, arterial PCO2 rises. Some portion of the inspired air volume goes to the air passages (trachea and major bronchi) and alveoli with little blood perfusing them, and thus doesn't contribute to removal of CO2 during exhalation. This portion is termed “dead space” gas. That portion of V that goes to well-perfused alveoli and participates in gas exchange is called the alveolar ventilation (VA) and exhaled gas that had participated in gas exchange in the alveoli is termed “alveolar gas”.
Monitoring and control of ventilation parameters as a function of measured expiratory CO2 is commonly used in ventilation systems. U.S. Pat. No. 4,112,938 describes a respirator that uses measurement of alveolar gas CO2 partial pressure as a means of adjusting a reservoir size to control inspiratory CO2 concentration. U.S. Pat. No. 5,320,093 describes a ventilator that adjusts inspiratory CO2 concentration so as to enhance a patient's natural ventilatory drive during recovery from anesthesia. In U.S. Pat. No. 5,402,796, a method is described which provides better accuracy of PaCO2 utilizing an initial calibration sample. U.S. Pat. Nos. 5,778,872, 6,612,308B2 and 6,799,570B2 portable ventilators that use reservoirs to store exhaled air for later use in rebreathing during inspiration so as to keep CO2 levels constant (“isocapnia”). U.S. Pat. No. 6,612,308B2 is further refined in U.S. Pat. No. 6,622,725B1 by providing a method for separating out the alveolar gas from the dead space gas, thus concentrating the expiratory CO2 for later rebreathing. U.S. Pat. No. 6,951,216B2 describes a ventilator utilizing a space-efficient CO2 exchanger that absorbs and stores expiratory CO2 gas that is later released into the inpsiratory gas stream to enhance CO2 concentrations.